CTNF 17/632,322 CTNF 99478 DETAILED ACTION Applicant is advised that the prior office action mailed on 02-27-2026 is vacated in favor of a new office action. After a telephonic interview with Applicants’ attorney of record, Janice Kugler DeYoung, on May 26, 2026, the examiner was notified that Kader et al. (Kader A et al., Reprod Biol Endocrinol , 2009), which appeared at pages 6 and 8 in the heading of the claims rejection under 102 and 103 in the Office Action mailed on 02/27/2026, was not the correct reference as applied to the 102 and 103 rejections made in the Office Action filed on 02-27-2026. Thus, Applicants requested clarification and correction. The examiner inadvertently supplied Kader et al. (Kader A et al., Reprod Biol Endocrinol , 2009) rather than Kader et al. (Kader A. et al., Fertil Steril . 2010 ) as the reference from which the teachings described the 35 U.S.C. 102 and 35 U.S.C. 103 rejections relied in the Office Action filed on 02-27-2026. Kader et al. (Kader A. et al., Fertil Steril . 2010 ) is the correct reference and the reference from which the teachings provided in the office action filed on 02-27-2026 and this current office action originate. A copy of Kader et al. (Kader A. et al., Fertil Steril . 2010; hereafter “ Kader et al.- 2010 ”) has been provided and the rejections have been edited to correctly reflect the reference. Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Election/Restrictions This action is in response to the papers filed on 03/31/2025. Claims 1-7, 9, 11-12, 14-27, and 29 are currently pending as per claims filed on 03/31/2025. Applicant's election with traverse of Group 1, claims 1-7, 9, 11-12, and 14-18 in the reply filed on 03/31/2025 was previously acknowledged. Applicant's traversal arguments are “Applicant respectfully disagrees with the Examiner's conclusions about the teachings of de Vries, Reinier Jet al. (Langmuir : the ACS journal of surfaces and colloids, 7354-7363).” However, because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 19-27 and 29 were previously withdrawn from consideration pursuant to 37 CPR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. The restriction is made final. Therefore, claims 1-7, 9, 11-12, and 14-18 are currently under examination to which the following grounds of rejection are applicable. Priority The instant application is a national stage entry under 35 USC 371 of PCT/US2019/064026 filed on 12/02/2019, which claims priority to PRO filed on 08/02/2019. Thus, the earliest possible priority for the instant application is 08/02/2019. Information Disclosure Statement The information disclosure statements (IDS) submitted on 05/12/2023, 07/09/2024, and 11/15/2024 were filed before the mailing date of the current office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Response to arguments Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments Claim Rejections - 35 USC § 102 Applicants allege that de Vries does not qualify as prior art under qualifies as prior art under 35 USC 102(a)(l). Applicants assert that Peony D. Banik, Sonal Nagpal, and Thomas M. van Gulik did not make any inventive contribution to the present invention. Additionally, the publication date ( June 11, 2019 ) is less than one year before the earliest priority date of the instant Application ( August 2, 2019 ). Therefore, a disclosure made 1 year or less before the effective filing date of a claimed invention shall not be prior art to the claimed invention under subsection (a)(l) if the disclosure was made by the inventor or joint inventor. As applicants argue, the de Vries et al. disclosure is a disclosure by the joint inventor within one year of the effective filing date of the priority application and as such does not qualify as prior art against the present application, Therefore, the rejection of claims 1, 3, 4, 7, 9, 11-12, and 14-18 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by de Vries et al. (de Vries RJ, Langmuir. 2019, IDS; hereafter “de Vries”) has been withdrawn. Claim Rejections - 35 USC § 103 In view of Applicants declaration under 37 C.F.R. § 1.130, the rejection of claims 2, 5-6 under 35 U.S.C. 103 as being unpatentable over de Vries et al. (de Vries RJ, Langmuir. 2019, IDS; hereafter “de Vries”) and Loretz et al. (Loretz LJ, Xenobiotica. 1989; hereafter “Loretz”). 12-256 AIA New Grounds of rejection Claim Rejections - 35 USC § 112 07-30-02 AIA The following is a quotation of 35 U.S.C. 112(b): (B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. Claims 1-7, 9, 11-12, and 14-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention Claim 1 and 2-7, 9, 11-12, and 14-18 (depend on claim 1) are indefinite in the recitation of “greater than about” for the following reason. “ About” encompasses values above and below a reference point whereas “greater than” encompasses only values above the reference point. Therefore, the combination of both terms (greater than about) is confusing because one term is including values below the reference point whereas the other term is excluding values below the reference point. Claim 2 is indefinite in the recitation of “less than about” for the following reason. “About” encompasses values above and below a reference point whereas “less than” encompasses only values below the reference point. Therefore, the combination of both terms (less than about) is confusing because one term is including values above the reference point whereas the other term is excluding values above the reference point. Claim 9 recites a plurality of “and/or” conjunctions. While this may be a convenient means for Applicant, such legalese renders the claims indefinite because the claimed first solution or second solution cannot contain simultaneously each of the structurally different molecules recited. To put it another way, the first solution, or first and second solutions or the first or second solution cannot contain both a UW solution and not contain a UW solution and. Appropriate correction is required. Claim Rejections - 35 USC § 102 07-06 AIA 15-10-15 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. 07-07-aia AIA 07-07 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-08-aia AIA (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. 07-15 AIA Claims 1, 5-6, 11, and 15-17 are re jected under 35 U.S.C. 102(a) (1) a s being an ticipated by Kader et al. (Kader A. et al., Fertil Steril . 2010; hereafter “ Kader et al.-2010 ” ) as evidenced by Ba laban et al. (Balaban B et al., Hum Reprod . 2008). Re garding Claim 1 and 5-6, Kader et al.- 2010 teaches a two-step vitrification method. Specifically, Kader et al.- 2010 teaches “The first step typically entails the use of relatively low concentrations of cryoprotectants—7.5% dimethylsulfide (DMSO) and 7.5% ethylene glycol (EG)—for 2–5 minutes, followed by an ultrashort (30–90 seconds') exposure to a second medium that contains a higher cryoprotectant concentration (usually double the initial concentration) as well as a dehydrating agent (commonly, a disaccharide, such as sucrose).The objective of this stepwise exposure is to avoid toxicity and osmotic shock.” (Pg. 2640, 3 rd paragraph). Kader et al.- 2010 teaches “Blastocysts were placed in a 20-mL droplet of equilibration solution ( First CPA Solution ) (7.5% DMSO, 7.5% EG, and 20% serum substitute supplement [SSS]) for either 4, 8, or 15 minutes. After equilibration, the blastocysts were propagated into three subsequent 20-mL droplets of vitrification solution ( Second CPA Solution ) (15% DMSO, 15% EG, and 20% SSS) , … and immediately transferred to liquid nitrogen.” (Pg. 2641, Vitrification and Warming) The CPA concentrations anticipates the concentrations recited in instant claims 5-6. The vitrification process using liquid nitrogen would inherently result in a cooling rate significantly faster than .1 Celsius per second as evidenced by Balaban et al. who teaches “Vitrification is an ultra-rapid method of cryopreservation whereby the embryo is transitioned from 37°C to −196°C in <1 s, resulting in extremely fast rates of cooling (>10 000°C/min).” Regarding Claim 11 , the droplet formation of less than 5 seconds would be an inherent effect method as taught by Kader et al.- 2010 absent evidence to the contrary. The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966). See M.P.E.P. § 2112.02. Regarding Claim 15-16, Kader et al.- 2010 teaches that after the mixing of cells and the second CPA solution, cells are transferred to LN2 (Pg. 2, Vitrification of blastomeres). Liquid nitrogen temperature is inherent at -196 Celsius. Therefore, this anticipates claim 15-16. Regarding Claim 17 , Kader et al.- 2010 teaches their methodology resulted in 100% cell survivability ( Abstract ) . Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. 07-20-aia AIA The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. 07-23-aia AIA The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. 07-20-02-aia AIA This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. 07-21-aia AIA Claim (s) 2, 4 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Kader et al. (Kader A. et al., Fertil Steril . 2010; hereafter “ Kader et al.-2010 ” ) as evidenced by Balaban et al. (Balaban B et al., Hum Reprod. 2008) as applied to claim 1 above and in view of Loretz et al. (Loretz LJ, Xenobiotica. 1989; hereafter “Loretz”, of record filed 05/07/2025) and Mamprin et al. (Mamprin ME et al., World J Gastroenterol. 2005) . Kader et al.- 2010 anticipates method of claim 1, as iterated above in the 102 rejection, the content of which is incorporated herein, in its entirety. Regarding Claim 2, 4 and 9, Kader et al.- 2010 teaches the first solution has exactly 15% of CPAs (Pg. 2640, 3 rd paragraph) . However, Kader et al.- 2010 does not specifically disclose the concentration of the CPA of the first solution is less than about 15% (v/v) as recited in instant claim 2. Kader et al.- 2010 does not teach the use of UW solution for the cryopreservation as in instant claim 9 or that the cells being preserved are hepatocytes as in instant claim 4. Mamprin et al. teaches that the use of UW solution for successful cryopreservation of cells, including hepatocytes, was well known in the art the time of the instant application (Pg. 1957, Introduction, Paragraphs 1-2). Loretz demonstrates an increased viability of recovered hepatocytes correlating with an increased concentration of CPA (e.g. DMSO to above 10%). At these concentrations, Loretz shows that both viability and metabolic activity increased with increasing concentrations of DMSO up to 10% following recovery of cryopreserved cells, with no adverse effects observed using 10%-20% DMSO ( Pg. 492, 1 st Paragraph ). It would have been obvious to a person of ordinary skill in the art prior to the filing date of the instant application to start with the vitrification method of Kader et al.- 2010 and then incorporated the UW solution as taught by Mamprin et al. and the teachings of Loretz with respect to CPA amounts resulting in a vitrification method capable of successfully preserving hepatocytes by increasing the combined CPA to above 10% (e.g. 5-10% of each, totaling 10-20% or 7.5% of each, totaling 15%) and including UW solution because this might increase the viability of the cells based on the teachings of the combined references. There would be reasonable expectation of success as it would have been a matter of combining known prior art elements according to known methods to yield predictable results and obvious to combine these methods as they seek to preserve the metabolic activity and produce a more viable cell population upon recovery . 07-21-aia AIA Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Kader et al. (Kader A. et al., Fertil Steril . 2010; hereafter “ Kader et al.-2010 ” ) as evidenced by Balaban et al. (Balaban B et al., Hum Reprod. 2008) as applied to claim 1 above and in view of Shi et al. (Shi M et al., J Mech Behav Biomed Mater . 2018) . Kader et al.- 2010 anticipates method of claim 1, as iterated above in the 102 rejection, the content of which is incorporated herein, in its entirety Regarding Claim 3 , Kader et al.- 2010 does not teach the droplets are an average diameter of .05mm to 10mm. Shi et al. teaches a droplet based vitrification for cell aggregates. The droplets formed by the method of Shi are 200uM, “We selected a fixed droplet diameter of 200 µm, which is within the size range of droplets generated by most systems such as microfluidics and cell printing system.” ( Pg. 384, 2 nd Column, 1 st full paragraph ). This is within the range of the instant application claim of between .05mm and about 10mm. While using this droplet size, Shi et al. taught “…upon vitrification, the maximum crystallization in cell aggregates (i.e., χ =1.9 ×10−4) was lower than the criterion of "innocuous intracellular ice formation (i.e., χ ≤10−3) proposed by Karlsson et al. (1994), which means the degree of ice formation in cell aggregates is not harmful for cell. These results indicate that vitrification has been successfully achieved in the current droplet-based vitrification of cell aggregates.” ( Pg. 387, 2 nd full paragraph ). It would have been obvious to a person of ordinary skill in the art prior to the filing date of the instant application to modify the vitrification method of Kader et al.- 2010 and to incorporate a fixed droplet diameter known in the art to be successful in cryopreservation methods as taught by Shi et al. as this fixed droplet diameter was shown to produce ice formation that was not harmful to cells and further “ results indicate that vitrification has been successfully achieved in the current droplet-based vitrification of cell aggregates .”. There would be reasonable expectation of success as it would have been a matter of combining known prior art elements according to known methods to yield predictable results . 07-21-aia AIA Claim s 7 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Kader et al. (Kader A. et al., Fertil Steril . 2010; hereafter “ Kader et al.-2010 ” ) as evidenced by Balaban et al. (Balaban B et al., Hum Reprod . 2008) as applied to claim 1 above and in view of Iussig et al. (Iussig B et al., Acta Obstet Gynecol Scand . 2019) as evidenced by Yong et al. (Yong KW et al., Cryobiology. 2020) Kader et al.- 2010 anticipates method of claim 1, as iterated above in the 102 rejection, the content of which is incorporated herein, in its entirety. Regarding Claims 7 and 12 , Kader et al.- 2010 . does not teach the use of sucrose combined with permeating CPAs for vitrification. However, Iussig et al. teaches that two-step vitrification methods utilizing sucrose in combination with other CPAs was well known in the art at the time of the instant application, “Currently, the most used protocol for oocyte vitrification has been described by Kuwayama and colleagues: it consists of a two-step procedure involving the stepwise addition of CPAs in cryomedia. After a first equilibration phase (5-15 min) in a solution containing 7.5% v/v ethylene glycol and 7.5% v/v DMSO, the oocytes are then moved to a vitrification solution with 15% v/v ethylene glycol and 15% v/v DMSO, plus 0.5 mol/L sucrose. After a brief incubation (up to 1 min) in the vitrification medium, the sample is then transferred onto specifically designed devices and finally plunged in liquid nitrogen at −196°C, where it is stored until use.” (Pg. 555, Section 4.2: Vitrification). Moreover, the use of sucrose as a non-permeating CPA (such as sucrose) in combination with permeating CPAs (such as ethylene glycol and DMSO) was well documented prior to the instant application as evidenced by a review of non-permeating CPAs by Yong et al ( Pg. 2, 2 nd full paragraph; Pg. 2 Non-permeating CPAs Section 2.1 ) . Yong et al. discloses “Non-permeating CPAs are large molecules that do not penetrate the plasma membrane and remain in the extracellular compartment during cooling to promote glass formation. Non-permeating CPAs include sugars (e.g., sucrose and trehalose) and high molecular weight (MW) polymers (e.g., polyvinyl pyrrolidone and Ficoll). Compared to permeating CPAs, they are relatively less cytotoxic. Their addition contributes to viscosity and tonicity, allowing lower concentrations of permeating CPAs to be used without compromising vitrification properties. Some studies reported that combining non-permeating and permeating CPAs further improved post-thaw viability and functionalities of vitrified embryos and ovarian tissues.” It would have been obvious to a person of ordinary skill in the art prior to the filing date of the instant application to modify the vitrification method of Kader et al.- 2010 and incorporate sucrose as taught by Iussig et al who demonstrates the addition of sucrose results in successful vitrification. Further, as it was well known in the art that the use of sucrose in combination with permeating CPAs would improve vitrification and subsequent recovery, there would be reasonable expectation of success as it would have been a matter of combining known prior art elements according to known methods to yield predictable results . 07-21-aia AIA Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Kader et al. (Kader A. et al., Fertil Steril . 2010; hereafter “ Kader et al.-2010 ” ) as evidenced by Balaban et al. (Balaban B et al., Hum Reprod. 2008) as applied to claim 1 above and as evidenced by Demirci et al. (Demirci U et al. Cell encapsulating droplet vitrification. Lab Chip . 2007, IDS filed on 05/12/23) Kader et al.- 2010 anticipates method of claim 1, as iterated above in the 102 rejection, the content of which is incorporated herein, in its entirety. Regarding Claim 14, Kader et al.- 2010 does not teach the specific cooling rate recited in instant claim 14, between 900°C/min and 1400°C/min. However, it was well known in the art at the time of the instant application that vitrification is affected by cooling rate, viscosity, and droplet volume as evidenced by Demirci et al. Demirci et al. teaches “Three factors affect vitrification: cooling rate, viscosity, and droplet volume. Increasing the cooling rate increases the probability of vitrification. This can be achieved by either increasing the viscosity (i.e., CPA molarity) or by decreasing the droplet size. The rate of heat transfer per unit area in an object is proportional to the temperature gradient across the object boundary, (qx/A) ∝ (dT/dx). This gives Fourier's law of cooling, qx = −kA(dT/dx), where qx is the rate of heat transfer in the x direction by conduction; k is the thermal conductivity; A is the area normal to the heat flow direction qx; T is the temperature; x is the conduction length. Integrating Fourier's law for spherical shell geometry gives the heat resistance of a droplet as , where rdroplet is the droplet radius and rcell is the radius of the cell residing in the droplet, Fig. 1a. Assuming a 10 µm-radius cell located at the droplet center, we plot heat resistance as a function of droplet diameter (Fig. 1a). Large droplets exhibit large heat resistance (Fig. 1a), which results in low ‘cooling rate’. Therefore, vitrification requires higher CPA concentration for large droplets than for small droplets.” ( Pg. 1428-1429, Theory section ). A person of ordinary skill in the art would have been motivated to determine an appropriate cooling rate through routine optimization within a vitrification method for cell cryopreservation, in order to effectively preserve cells in such a way that survivability would be minimally impacted. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.") See MPEP 2144.05 II. A. Conclusion Claims 1-7, 9, 11-12 and 14-18 are rejected. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KODYE LEE ABBOTT whose telephone number is (703)756-1111. The examiner can normally be reached M-F 8-5. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G. Leavitt can be reached on (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /KODYE LEE ABBOTT/Examiner, Art Unit 1634 /MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634 Application/Control Number: 17/632,322 Page 2 Art Unit: 1634 Application/Control Number: 17/632,322 Page 3 Art Unit: 1634 Application/Control Number: 17/632,322 Page 4 Art Unit: 1634 Application/Control Number: 17/632,322 Page 5 Art Unit: 1634 Application/Control Number: 17/632,322 Page 6 Art Unit: 1634 Application/Control Number: 17/632,322 Page 7 Art Unit: 1634 Application/Control Number: 17/632,322 Page 8 Art Unit: 1634 Application/Control Number: 17/632,322 Page 9 Art Unit: 1634 Application/Control Number: 17/632,322 Page 10 Art Unit: 1634 Application/Control Number: 17/632,322 Page 11 Art Unit: 1634 Application/Control Number: 17/632,322 Page 12 Art Unit: 1634 Application/Control Number: 17/632,322 Page 13 Art Unit: 1634 Application/Control Number: 17/632,322 Page 14 Art Unit: 1634 Application/Control Number: 17/632,322 Page 15 Art Unit: 1634 Application/Control Number: 17/632,322 Page 16 Art Unit: 1634
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